Acoustic activation is a means to improve the effectiveness of drugs.
A variety of acoustically activated drug delivery systems exist including gas bubbles and drugs, drugs encapsulated in microspheres, biodegradable polymer and drug solution gas bubbles, drug impregnated microsponges, injectable nanoparticles such as vesicles, micelles, and liposomes, and other drug carrying particles, bubbles, or spheres that permit acoustic activation of therapeutic agents.
Acoustically activated drug delivery systems are typically administered to a patient and then activated by extracorporeal ultrasound sources to increase the permeability of cell membranes to allow drugs to better penetrate cells, enhance drug uptake, and hence improve the treatment efficacy.
Acoustic activation may permit localized drug delivery. The physician may apply ultrasound once the drug and cavitation nuclei, typically microbubbbles, are delivered to a point of interest within a patient, in order to release the drug at the disease site. Localized drug delivery permits a high dosage of toxic drugs to improve treatment effectivness and may minimize negative side effects to healthy tissue.
Ultrasound energy may cause gas microbubbles to resonate or burst into smaller fragments, and may induce cavitation, microstreaming, or the perforation of cell membranes. Bubble resonance is typically described as sonoporation or non-inertial cavitation, while the bubble destruction is described as inertial cavitation.
The therapeutic agents may be chemotherapy drugs, gene therapy, and other agents.
Direct injection of chemotherapy drugs into tumours is typically not done, as this does not improve patient outcome. Cancers may develop resistance to drugs and render chemotherapy useless. Acoustic activation researchers have destroyed human, drug-resistant tumours in rodents using cavitation nuclei and ultrasound.
Acoustic activation technology shows promise for the treatment of drug resistant cancer tumours, vascular disease, neurological diseases, and other diseases. Efficacy may be enhanced by infusing drugs with bubbles and enhancing cell permeability with ultrasound energy. Further benefits may be obtained by infusing transient gas microbubbles in combination with acoustically activated drug delivery release systems to enhance the local cavitation effects.
Presently, acoustically activated drug delivery systems are typically hard-shelled, persistent, gas microbubbles formulated in a pharmaceutical setting. They are designed to persist through to administration to a patient. Such products are required to maintain integrity through the shock, vibration, and temperature changes of transportation and to persist over time through to administration. Such formulations may include complex design and processing features, for example, are typically polymer or polymer and solvent based. However, these persistent systems must also dissipate or degrade in the patient once administered and activated. These polymers and any other components are required to biodegrade with minimal negative side effects.
Acoustically activated drug delivery systems may range in size from nano scale, sub micron, up to 1000 microns, with a one to ten micron size typical. Size preference depends upon the resonant frequency, or a harmonic, of the bubble or particle to be activated at a particular ultrasound frequency, and may also depend upon the desired release rates of the encapsulated drugs. Increased size uniformity would encourage effective and more complete activation.
Acoustic activation techniques include inertial cavitation, where typically 20 micron gas microbubbles are destroyed by ultrasound energy, and non-inertial cavitation or sonoporation, where ultrasound energy causes one to seven micron microbubbles to resonate. Researchers have demonstrated in vivo therapeutic enhancement with both techniques. In addition, sonophoresis involves the application of ultrasound, or ultrasound and cavitation nuclei such as microbubbles, to increase the permeability of surface cells, such as the skin or cornea, in order to improve the delivery of topically applied drugs.
In the field of oncology, treatment techniques may include administration to patients of individual ‘cocktails’ of chemotherapy drugs depending upon the indication, patient reaction to therapy, and disease stage. Future treatment planning may include the administration of a first chemotherapy drug enhanced by inertial cavitation followed by a second drug enhanced by non-inertial cavitation.
Oncologists do not currently have a means to provide patients with a flexible, acoustically activated therapy, i.e. the means to administer a variety of drugs, or combination of drugs, on short notice, with therapeutic enhancements such as improved drug uptake and reduced side effects.
Photodynamic drugs are light activated by laser or other sources in order to improve their effectiveness. They are limited to surface applications of about one centimeter in depth or, through the use of a balloon catheter equipped with a laser, may be used to treat internal surfaces of the body for diseases such as cancer of the esophagus. The means to improve the cellular uptake of photodynamic drugs using acoustic activation may improve their effectiveness. The means to light activate photodynamic drugs at a depth within a patient would expand their potential usage.
High intensity focused ultrasound (HIFU) is a means to induce cell necrosis in diseased tissue, for example to destroy tumours through heat ablation. Heat ablation treatments typically require a duration of minutes, which may preclude multiple direct probe applications if patients are in overall poor health and require a number of tumours to be destroyed. The simultaneous infusion of gas microbubbles with HIFU energy may enhance the treatment efficacy and expand potential applications.
Accordingly, there is a need for a medical device that would overcome these and other drawbacks.